The Development of Next‐Generation Pyridinium‐Based multiQAC Antiseptics

Abstract

A series of 18 bis- and tris-pyridinium amphiphiles were prepared and tested for both antimicrobial activity and lytic capability, in comparison with the commercially available pyridinium antiseptic cetylpyridinium chloride (CPC). Assessments were made against Gram-positive and Gram-negative bacteria, including two methicillin-resistant Staphylococcus aureus (MRSA) strains. While 2Pyr-11,11 was identified as one of the most potent antimicrobial quaternary ammonium compounds (QACs) reported to date, boasting nanomolar inhibition against five of six bacteria tested, no significant improvement in bioactivity of tris-pyridinium amphiphiles over their bis-pyridinium counterparts was observed. However, the multicationic QACs (multiQACs) presented herein did display significant advantages over the monocationic CPC; while similar red blood cell lysis was observed, superior activity against both Gram-negative bacteria and resistant S. aureus strains led to the discovery of four pyridinium-based multiQACs with advantageous therapeutic indices.

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

“…Membrane-lysing agents, including quaternary ammonium cations (QACs), have been shown to rapidlyk ill persister cells and eradicate bacterial biofilms ( Figure 3A). [87][88][89][90][91][92] Typically, potent QAC biofilm-eradicatinga gentsd emonstrate hemolysis, or the lysis of red blood cells, whichi saconcern for therapeutic development. [87,91,92] However, there is hope for QACc ompounds as therapeutic agents, as these compounds operate through similarm echanismst oa ntimicrobialp eptides (AMPs), which are naturallyo ccurring membrane-active antimicrobial agentsu tilized by the mammalian immune response to eradicate microorganisms during infection.…”

Synthesis and Antibacterial Evaluation of Bis‐thiazolium, Bis‐imidazolium, and Bis‐triazolium Derivatives

“…Mono-ammonium compounds such as benzalkonium chloride or cetylpyridinium chloride were followed by bis-ammonium compounds such as dequalinium chloride and chlorhexidine. [9,10] In addition, other recente fforts led to the designo fp owerful molecules that show very low toxicity toward mammalian cells. They also suggest that some derivatives of this class could be used foro ther purposes than simple topical administration.…”

“…[9] Considering compounds with the same linker length, derivatives bearinga4-tert-butylbenzyl moiety are slightly more active than those with a2 -methylnaphthalenyl group (for example, compare 33 with 36, 34 with 37,a nd 40 with 43). a) K 2 CO 3 ,DMF, D;b)CH 3 CN, D. tested strains, with MICs around 1 mgmL À1 .B esides, both strains of P. aeruginosa appeared to be less sensitive;h owever, some compounds exhibitedl ow to very low MICs.…”

“…Thus, some efforts have been made to correlate the structural features of QACs and both their antibacterial activity and eukaryotic toxicity. [9,10] In addition, other recente fforts led to the designo fp owerful molecules that show very low toxicity toward mammalian cells. [11] Besides, QACs maye xhibit antimalarial activity,a nd someb is-cationicd erivatives provedt ob e very potent both in vitro and in vivo.…”

“…In either case, the positive chargei ss pread over the heterocyclic structure, as in QACs bearing ap yridinium structure. [9] Considering compounds with the same linker length, derivatives bearinga4-tert-butylbenzyl moiety are slightly more active than those with a2 -methylnaphthalenyl group (for example, compare 33 with 36, 34 with 37,a nd 40 with 43). Nevertheless, it is clear that independento ft hese two substituents, al ongerl inker is associated with higherp otency.F or the compounds bearing ad ecyl substituent (compounds 38 and 45), only one linker (n = 10) was envisioned;remarkably,t hese compounds were found to be the most active, especially against both strains of P. aeruginosa.…”